Breast cancer ranks second among cancer deaths in women. Recent data suggest that mortality rates have declined significantly in both white and black women, perhaps due to early detection and improved treatment. However, statistical analysis with the SEER(Surveillance, Epidemiology, and End Results) program and the American Cancer Society (ACS) survey suggest that black Americans are more likely to develop and die from cancer than persons of any other racial and ethnic group. There are many factors that contribute to the poor outcome of Black Americans. We are interested in elucidating what these factors are and their role in breast cancer. Patients with overexpression of HER-2/neu (member of the Epidermal Growth Factor Receptors) in their cancerous breast tissue have poorer outcomes. Recently, clinical and translational studies from our laboratory and others have demonstrated that an increase in plasma HER-2/neu is associated with poor outcome and reduction in disease-free survival in African American and Hispanic women mith breast cancer. However, the mechanisms associated with the HER-2/neu-mediated aggressive tumor growth and poor outcome are poorly understood. We have postulated that alterations in downstream signal transduetion pathway(s) may contribute to increased cell proliferation and resistance to treatment. In particular, protein kinase B or Akt may play a critical role in HER-2/neu overexpressing tumors. Targeting Akt may slow down oncogenic signals resulting from HER-2/neu activation. We will therefore study the role of Akt in proliferation, survival and etiology of HER-2/neu overexpressing breast tumors. This study will be conducted on clinical samples from cancer patients; in vitro cell culture models; and in vivo mouse mammary tumor model using 3 specific aims: (1) To establish a clinical correlation between tissue overcxpression of HER-2/neu and Akt activation. (2) To investigate the effects of Herceptin (Trastuzumab, antibody against HER-2/neu) alone and in combination with chemotherapy drugs on cell proliferation and apoptosis in breast cancer cells overexpressing HER-2/neu. (3) To develop a mouse model to study the physiological functions of Akt in the development and pathogenesis of breast cancer in vivo.